CN101007187B - Preparation method of composite drug-eluting stent and its drug coated layer - Google Patents
Preparation method of composite drug-eluting stent and its drug coated layer Download PDFInfo
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- CN101007187B CN101007187B CN200710036854.5A CN200710036854A CN101007187B CN 101007187 B CN101007187 B CN 101007187B CN 200710036854 A CN200710036854 A CN 200710036854A CN 101007187 B CN101007187 B CN 101007187B
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Abstract
The invention discloses a making method of drug coating on the elution rack, which comprises the following steps: dissolving vitamin A acid drug and polymer in the organic solvent to obtain the coating liquid of vitamin A acid; coating the liquid on the predisposed metal rack surface; evaporating solvent; obtaining the buried vitamin A acid coating; dissolving estrogen drug and polymer in the organic solvent to obtain estrogen coating liquid; coating on the surface of estrogen coating liquid; evaporating; obtaining the product; or dissolving vitamin A acid, estrogen drug and polymer in the organic solvent to obtain the composition of drug and polymer; coating on the predisposed metal rack surface; evaporating; burying in the drug coating of vitamin A acid and estrogen.
Description
[technical field]
The present invention relates to medical FirebirdTM field, specifically the medication coat on FirebirdTM.
[background technology]
In recent years, along with the change of growth in the living standard and life style, the atherosis cardiovascular disease as representative of take became life-threatening primary factor.Patients with coronary artery disease for moderate and moderate, adopt the interventional therapy of the nervous art (PTCA) of percutaneous arteria coronaria and intravascular stent implantation (stenting) have advantages of that wound is little, it is fast to recover, applied widely, just becoming the focus of current coronary heart disease treatment.
Then the generation of postoperative restenosis is but the matter of utmost importance that interventional therapy faces, according to statistics, after the nervous art (PTCA) of the incidence rate percutaneous arteria coronaria of PTCA and support postoperative restenosis and bare metal stent implantation, there is respectively 30～70% and 10～30% patient that the again narrow even inaccessible for the treatment of place blood vessel can occur, need further again interventional procedure treatment or surgical operation therapy.
The definite mechanism that restenosis occurs it be unclear that, the endodermis that while thinking at present interventional procedure, balloon expandable causes is torn, and further platelet deposition, thrombosis, smooth muscle proliferation and a series of pathological processes such as migration, extracellular matrix formation on this basis, causing Neointimal formation, is the principal element that causes restenosis.
2003 and 2004, U.S. FDA passed through respectively the authentication of Cordis company observation on sirolimus-eluting stent (Cypher) and Boston Scientific company Paclitaxel-Eluting (Taxus).Such bracket for eluting medicament (DES) will act on the medicine of each link of restenosis, comprise immunosuppressant, anti-inflammatory agent, antiproliferative agents, anti-migration medicine, intercellular matrix regulator and short endothelialization medicine, be attached to metal support surface by the whole bag of tricks, make medicine be directly released into the vascular lesion position from rack surface, improve pharmaceutically-active targeting, avoiding the whole body toxic and side effects of oral medication, is the most successful method of generation of prevention of restenosis.A large amount of clinical showing, two kinds of bracket for eluting medicament of Cypher and Taxus have great anti-restenosis performance, and the incidence rate of postoperative restenosis, lower than 10%, can meet the demand of current clinical anti-restenosis aspect.
But the BASKET-LATE clinical research that the sick meeting of the american heart of 2006 is announced shows, after the patient stops using clopidogrel, bracket for eluting medicament death and heart infarction incidence rate are apparently higher than the bare bracket group.There are some researches show in addition, bracket for eluting medicament late period the thrombus in stents incidence rate higher than the bare bracket group.There is the scholar to think owing to no matter being rapamycin or paclitaxel, in the strong inhibition vascular smooth muscle cell proliferation, also propagation and the migration of strong inhibition vascular endothelial cell, cause the blood vessel delay of endothelialization again, and the delay of endothelialization again, the important risk factor of bracket for eluting medicament MACE in late period event just.
Therefore under the prerequisite of the superior anti-restenosis performance that guarantees current bracket for eluting medicament, the medicine and the medicine that accelerate the process of endothelialization again in the bracket for eluting medicament body are the standards of current bracket for eluting medicament Chinese medicine screening.Therefore but also do not have at present a kind of drug alone can meet above-mentioned requirements, medicine and the anti-restenosis medicaments that need to will urge endothelialization by the method for drug regimen are prepared into the up-to-date focus that Mixed-eluting stent is current bracket for eluting medicament research under certain condition.
Retinoic acid is the acid that the oxidation of vitamin A terminal hydroxyl obtains, and has biological effect widely, can suppress cell migration, propagation, platelet aggregation, thrombosis, and inflammation and angiogenesis, regulate the formation of extracellular matrix.The in vitro study retinoic acid has very strong anti-smooth muscle proliferation effect, and its half-inhibition concentration to human aortic smooth muscle cell's propagation is IC
50for 22nM (Cardiocasc Res, 2001,49 (4): 851-62), suitable with rapamycin.Report in addition that in addition retinoic acid can promote endothelial growth, but still disputable in this respect.
Estrogen is a class endogenous sex hormones, cardiovascular system is had to the effect of comprising, can improve nitricoxide synthase (eNOS) level at endothelial injury position, strengthen the fixing and differentiation of circulation endothelium progenitor cell in blood, promote the endothelialization of injured blood vessel part, suppress propagation, migration and the blood vessel negativity of vascular smooth muscle cell and reinvent, suppress the inflammatory reaction of blood vessel part.
The present invention combines use by retinoic acid medicine and estrogenic, is prepared into a kind of Mixed-eluting stent.This bracket for eluting medicament discharges in vitro to maintain and discharges an effect in month, has stronger anti-restenosis performance in body, and blood vessel endothelialization is good again, meet the clinical research needs, there is market prospect preferably.
[summary of the invention]
The object of the present invention is to provide a kind ofly to there is certain anti-restenosis performance, and the blood vessel good composite drug-eluting stent of endothelialization degree and the preparation method of medication coat thereof again after stenting.The contained activity of this bracket for eluting medicament becomes as a kind of drug regimen, and this drug regimen is comprised of retinoid medicine and estrogens medicine.
The in vitro study retinoid has very strong anti-smooth muscle proliferation effect, and its intensity and rapamycin to human aortic smooth muscle cell's propagation is suitable.Retinoic acid can suppress cell migration, propagation, platelet aggregation in addition, thrombosis, and inflammation and angiogenesis, regulate the formation of extracellular matrix, acts on a plurality of paths that restenosis occurs.The estrogens medicine can improve the nitricoxide synthase level at endothelial injury position, strengthen the fixing and differentiation of circulation endothelium progenitor cell in blood, promote the endothelialization of injured blood vessel part, suppress propagation, migration and the blood vessel negativity of vascular smooth muscle cell and reinvent, suppress the inflammatory reaction of blood vessel part.
Early-stage Study of the present invention, show retinoid medicine and estrogens medicine are combined to use, in range of doses, can when suppressing vascular smooth muscle cell, promote the propagation of vascular endothelial cell.The bracket for eluting medicament prepared with this two classes Drug combination has certain anti-restenosis performance in vivo, and after stenting blood vessel the endothelialization degree is good again.
Retinoid medicine of the present invention, be the vitamin A intermediate product of metabolism in vivo, in the form neurogenesis and development process of Various Tissues, plays a significant role.The retinoic acid structural formula is comprised of the whole last group of ring-type, polyenoid side chain and whole last group three parts of polarity, chemical structural formula and Relation between Biological Activity are close, when this three part is replaced by different groups, can obtain the different compound of biological activity, retinoid compounds is divided into the three generations according to the structure difference at present, first is replaced by different groups on behalf of the polarity end, and its representative is 13-cisRA; Second on behalf of the eventually change of last group of ring-type, as etretinate etc.; Third generation retinoic acid is that the polyenoid side chain is replaced by aromatic rings, as aryltretinoin ethylester (Arotinoidethylester, Ro13-6298).Wherein the most important thing is 13-cisRA (13-cRA), all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9-cRA).
Estrogens medicine of the present invention is selected from natural origin, synthetic and plant origin estrogen.Estrogenic of the present invention, comprise estradiol, estriol, estrone, estradiol benzoate, estradiol valerate, dipropionate estradiol, nilestriol, ethinylestradiol, female three methyl ethers of alkynes, ethinylestradiol methyl ether, diethylstilbestrol and structural derivative and analog; Also comprise that the plant origins such as resveratrol, soybean isoflavone, Radix Puerariae flavone have the medicine of estrogen activity.
Support of the present invention can be that coronary artery bracket, cerebral arteries support, carotid stents or iliac artery support etc. are any for maintaining the angiocarpy bracket of vascular patency.Described support is metal rack, and its material is selected from the metal materials such as cobalt, Nitinol, medical stainless steel.
Medication coat of the present invention can be by adopting following method preparation: (1) first is dissolved in retinoic acid medicine and polymer in organic solvent and obtains the retinoic acid coating solution, be applied to pretreated metal support surface by methods such as spraying, dip-coating, brushings, obtain being embedded in the retinoic acid medication coat after solvent evaporates; (2) again estrogenic and polymer are dissolved in organic solvent and obtain the estrogen coating solution, by methods such as spraying, dip-coating, brushings, be applied to retinoic acid medication coat surface, obtain being embedded in estrogenic medication coat after solvent evaporates.
Can also prepare by the following method of employing by medication coat of the present invention: retinoic acid, estrogenic and polymer are dissolved in organic solvent simultaneously to the mixture that obtains medicine and polymer, be applied to pretreated metal support surface by methods such as spraying, dip-coating, brushings, obtain being embedded in retinoic acid and estrogenic medication coat simultaneously after solvent evaporates.
In addition, can the precoating layer bottom at medicine layer and backbone metal support, for increasing the bond strength of medicated layer and metal, strengthen the compliance of medication coat when support pressure is held and expand; In the outside of medicated layer, can also introduce one or more layers straight polymer carrier coating, for regulating drug coating Chinese medicine rate of release, reduce the generation of burst drug release phenomenon.
Medication coat of the present invention, its gross thickness is 1～100um, and wherein the thickness of pharmaceutical polymer mixed coating is 1～90um, and in whole coating, the shared total amount percentage ratio of retinoic acid is 1～40%, and the shared percentage by weight of estrogen is 0.1～40%.
Solvent of the present invention, comprise alcohol, ether, ester, ketone and heterocyclic organic solvent, such as oxolane, ethyl acetate, acetone, dichloromethane and chloroform etc.
Polymer support of the present invention, it can be biodegradable polymer carrier, be selected from polyester, poly-anhydride, polyamino acid, poly phosphazene, poly-polysaccharide etc. and copolymer and mixture, comprise one or more of polylactic acid, polyglycolic acid, poly-(lactic acid-ethanol), polycaprolactone, chitosan, glucosan, chitin, poly-capric anhydride, polyvinyl alcohol etc. or its mixture; It can be also Biostatic polymer, be selected from polyurethanes, polyolefin, polyester, polyamide, polycaprolactam, polyimides, polyvinyl methyl ether, polyvinyl alcohol or vinyl alcohol, olefin copolymer, polyacrylonitrile, polydimethylsiloxane, poly-(ethylene-vinyl acetate), the polymer based on acrylate or copolymer, polyvinylpyrrolidone, fluorinated polymer, cellulose esters, porous ceramics coating, the poly-charcoal of fluorine, or one or more of its mixture.
The present invention preferably is combined as the drug regimen of all-trans-retinoic acid and estradiol.The all-trans-retinoic acid estradiol composite drug-eluting stent release in vitro of preparation can be more than 4 weeks on this basis, the generation and the endothelialization degree that obviously suppress new intima in body are good, meet clinical anti-restenosis requirement, there is certain potential applicability in clinical practice, be expected to reduce the financial burden of the dual antiplatelet drug of the postoperative long-term taking of patient.
Because retinoic acid character is unstable, be subject to illumination effect very large, therefore, about each process of retinoic acid bracket for eluting medicament, comprise coating solution configuration, bracket coating, assay, vitro release research and retinoic acid is set on sacculus, all need to carry out in darkroom.
[accompanying drawing explanation]
Fig. 1 is all-trans-retinoic acid-estradiol Mixed-eluting stent release in vitro curve chart.
Fig. 2 is that all-trans-retinoic acid-estradiol Mixed-eluting stent is implanted the miniature pig arteria coronaria support vessel segment transverse section of 4 weeks section light microscopic figure (HE dyeing, * 25 times).
Fig. 3 is the scanning electron microscope (* 500) that all-trans-retinoic acid-estradiol Mixed-eluting stent is implanted the miniature pig support vessel segment endothelial cell growth of 4 weeks.
[specific embodiment]
Embodiment 1
Take respectively appropriate all-trans-retinoic acid and PLA by the weight ratio of 1: 4, being settled to solids content percentage ratio with the oxolane dissolving is that 1%. employing atomizing spraying devices spray to pretreated bare metal stent surface by the retinoic acid coating solution, room temperature vacuum solidification drying again, obtain retinoic acid layer coating. take respectively appropriate estradiol and PLA by the weight ratio of 1: 4, being settled to solids content percentage ratio with the oxolane dissolving is that 1%. employing atomizing spraying devices spray to the support retinoic acid coating outside by the estradiol coating solution, room temperature vacuum solidification drying again, obtain all-trans-retinoic acid estradiol Mixed-eluting stent 1.
Embodiment 2
Take respectively appropriate all-trans-retinoic acid and polyacrylic resin silicon dioxide nano composite material by the weight ratios of 4: 6, being settled to solids content percentage ratio with the oxolane dissolving is that 1%. employing atomizing spraying devices spray to pretreated bare metal stent surface by the retinoic acid coating solution, room temperature vacuum solidification drying again, obtain retinoic acid layer coating. take respectively appropriate estradiol and polyacrylic resin silicon dioxide nano composite material by the weight ratios of 3: 7, being settled to solids content percentage ratio with the oxolane dissolving is that 1%. employing atomizing spraying devices spray to the support retinoic acid coating outside by the estradiol coating solution, room temperature vacuum solidification drying again, obtain all-trans-retinoic acid estradiol Mixed-eluting stent 2.
Embodiment 3
Take respectively appropriate all-trans-retinoic acid, estradiol and polyacrylic resin silicon dioxide nano composite material by the weight ratio of 1: 1: 3, being settled to solids content percentage ratio with the oxolane dissolving is that 1%. employing atomizing spraying devices spray to pretreated bare metal stent surface by hybrid medicament smear layer liquid, room temperature vacuum solidification drying again, obtain hybrid medicament smear layer. take the polyacrylic resin silicon dioxide nano composite material appropriate, obtaining percentage by weight with the oxolane ultrasonic dissolution is 0.5% coating solution.Adopt aforementioned coating process polyacrylic resin silica nanometer coating solution to be coated onto to the drug stent surface that coats all-trans-retinoic acid estradiol layer coating, obtain all-trans-retinoic acid estradiol Mixed-eluting stent 3.
Embodiment 4
Referring to Fig. 1, (methanol: 0.05MpH7.4PBS=20: 80), for medium, carry out vitro release research in 37 ℃ of water bath chaders, frequency of oscillation is 100RPM will to prepare 10ml20% methanol for retinoic acid estradiol Mixed-eluting stent.Interval in accordance with regulations takes out whole media and supplements synthermal 20% methanol of equal-volume.Sample-20 are ℃ freezing, before mensuration, thaw and 15000rpm * 10min centrifugal, the supernatant sample introduction.The all-trans-retinoic acid FirebirdTM release in vitro curve of example 2 preparations is shown in accompanying drawing 1.
Referring to Fig. 2, Fig. 3.Estimate endothelialization effect in all-trans-retinoic acid-anti-Neointimal formation of estradiol Mixed-eluting stent and body in miniature pig coronary artery injury model.Coronary artery is implanted to overdistension, and the support blood vessel diameter is than being 1.2-1.3: 1.The result demonstration, retinoic acid-estradiol Mixed-eluting stent was implanted after 4 weeks can obviously suppress Neointimal formation, and the endothelialization degree of this Mixed-eluting stent is good, sees Fig. 2,3.
Claims (6)
1. a composite drug-eluting stent, comprise medication coat and support, described medication coat is comprised of contained active component and polymer, it is characterized in that contained active ingredient is a kind of drug regimen, described drug regimen is comprised of retinoid medicine and estrogens medicine, in whole coating, the shared percentage by weight of retinoid medicine is 1～40%, the shared percentage by weight of estrogens medicine is 0.1～40%, described retinoid medicine is retinoic acid and derivant thereof, described retinoic acid and derivant thereof are all-trans-retinoic acid, described estrogens medicine is for having the bioactive medicine of estrogen, it is described that to have the bioactive medicine of estrogen be estradiol.
2. the preparation method of the medication coat of composite drug-eluting stent according to claim 1, it is characterized in that comprising the following steps: (1) is dissolved in all-trans-retinoic acid and polymer in organic solvent and obtains the all-trans-retinoic acid coating solution, be applied to pretreated metal support surface by spraying, dip-coating or brushing method, obtain being embedded with the medication coat of all-trans-retinoic acid after solvent evaporates; (2) again estradiol and polymer are dissolved in organic solvent and obtain the estradiol coating solution, by spraying, dip-coating or brushing method, be applied to all-trans-retinoic acid medication coat surface, obtain being embedded with the medication coat of estradiol after solvent evaporates.
3. the preparation method of the medication coat of composite drug-eluting stent according to claim 1, it is characterized in that comprising the following steps: all-trans-retinoic acid, estradiol and polymer are dissolved in organic solvent simultaneously to the mixture that obtains medicine and polymer, be applied to pretreated metal support surface by spraying, dip-coating or brushing method, obtain being embedded with the medication coat of all-trans-retinoic acid and estradiol simultaneously after solvent evaporates.
4. according to the preparation method of the medication coat of claim 2 or 3 described composite drug-eluting stents, it is characterized in that described polymer is Biostatic polymer carrier or biodegradable polymer carrier.
5. the preparation method of the medication coat of composite drug-eluting stent according to claim 4, is characterized in that described Biostatic polymer carrier is selected from one or more of polyolefin, polyester, polyamide, polyimides, polyvinyl methyl ether, polyvinyl alcohol, polyacrylonitrile, polydimethylsiloxane, the polymer based on acrylate or copolymer, polyvinylpyrrolidone, fluorinated polymer, cellulose esters or its mixture.
6. the preparation method of the medication coat of composite drug-eluting stent according to claim 4, is characterized in that biodegradable polymer carrier is selected from one or more in polycarboxylic acids, collagen, gelatin, polycarboxylate, poe, poly-anhydride, polyamino acid, poly-polysaccharide, polysaccharide, poly phosphate, polyphosphazene.
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102143768A (en) | 2008-07-03 | 2011-08-03 | 维塞尔泰克生物医学有限责任公司 | Controlled and localized release of retinoids to improve neointimal hyperplasia |
| CN103948966B (en) * | 2014-05-07 | 2015-10-28 | 柳毅 | The preparation method of retinoic acid hydroxylapatite bionic compound and this bionical complex |
| CN104524646A (en) * | 2014-06-03 | 2015-04-22 | 东莞天天向上医疗科技有限公司 | Biodegradable drug eluting stent and manufacturing method thereof |
| CN105771005A (en) * | 2016-03-24 | 2016-07-20 | 乐普（北京）医疗器械股份有限公司 | Anti-rheumatic blood vessel stenosis drug-eluting stent and preparation method and application thereof |
| CN113304307B (en) * | 2021-05-21 | 2022-03-25 | 浙江大学 | Polyphosphazene-based hydrogel wound dressing with antibacterial and wet surface adhesion properties and preparation method thereof |
| CN116712620B (en) * | 2023-04-27 | 2023-12-12 | 雅伦生物科技(北京)有限公司 | Drug coating, drug eluting stent containing same and preparation method thereof |
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| CN1367023A (en) * | 2002-03-08 | 2002-09-04 | 清华大学 | Preparation method of biodegradable medicine composite macromolecular scaffold material |
| CN1568166A (en) * | 2001-10-15 | 2005-01-19 | 荷姆泰克股份有限公司 | Coating of stents for preventing restenosis |
| CN1669597A (en) * | 2004-03-16 | 2005-09-21 | 程树军 | Medicine eluted cardiovascular support |
| WO2005086831A2 (en) * | 2004-03-10 | 2005-09-22 | Orbus Medical Technologies, Inc. | Endothelial ligand binding coated medical device |
| CN1672746A (en) * | 2004-03-22 | 2005-09-28 | 科迪斯公司 | Local vascular delivery of panzem in combination with rapamycin to prevent restenosis following vascular injury |
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2007
- 2007-01-26 CN CN200710036854.5A patent/CN101007187B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1568166A (en) * | 2001-10-15 | 2005-01-19 | 荷姆泰克股份有限公司 | Coating of stents for preventing restenosis |
| CN1367023A (en) * | 2002-03-08 | 2002-09-04 | 清华大学 | Preparation method of biodegradable medicine composite macromolecular scaffold material |
| WO2005086831A2 (en) * | 2004-03-10 | 2005-09-22 | Orbus Medical Technologies, Inc. | Endothelial ligand binding coated medical device |
| CN1669597A (en) * | 2004-03-16 | 2005-09-21 | 程树军 | Medicine eluted cardiovascular support |
| CN1672746A (en) * | 2004-03-22 | 2005-09-28 | 科迪斯公司 | Local vascular delivery of panzem in combination with rapamycin to prevent restenosis following vascular injury |
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